The
tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this family encode dimeric
proteins consisting of two closely related subunits (α and β), representing the major constituents of microtubules.
Tubulin genes play a crucial role in the mechanisms of the Central Nervous System development such as neuronal migration and axonal guidance (axon outgrowth and maintenance). Different mutations in α/β-
tubulin genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, and TUBB) might alter the dynamic properties and functions of microtubules in several ways, effecting a reduction in the number of functional
tubulin heterodimers and causing alterations in
GTP binding and disruptions of the binding of other
proteins to microtubules (motor
proteins and other microtubule interacting
proteins). In recent years an increasing number of brain malformations has been associated with mutations in
tubulin genes:
malformations of cortical development such as
lissencephaly and various grades of gyral disorganization, focal or diffuse
polymicrogyria and open or closed-lips
schizencephaly as likely consequences of an altered neuronal migration process; abnormalities or agenesis of the midline commissural structures (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, dysmorphisms of the hind-brain as expression of axon guidance disorders. Dysmorphisms of the basal ganglia (fusion between the caudate nucleus and putamen with absence of the anterior limb of the internal capsule) and hippocampi were also observed. A rare form of
leukoencephalopathy characterized by hypomyelination with
atrophy of the basal ganglia an cerebellum (H-ABC) was also recently described. The present review, describing the structural and functional features of
tubulin genes, aims to revise the main cerebral associated malformations and related clinical aspects, suggesting a genotype-phenotype correlation.